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Glycobiology, 2001, Vol. 11, No. 12 1051-1070
© 2001 Oxford University Press

Modeling human congenital disorder of glycosylation type IIa in the mouse: conservation of asparagine-linked glycan-dependent functions in mammalian physiology and insights into disease pathogenesis

Yan Wang2, Jenny Tan3, Mark Sutton-Smith4, David Ditto5, Maria Panico4, Robert M. Campbell2, Nissi M. Varki6, Jeffrey M. Long2,7,8, Jaak Jaeken9, Simon R. Levinson10, Anthony Wynshaw-Boris2,7,8, Howard R. Morris4, Dzung Le5, Anne Dell4, Harry Schachter3 and Jamey D. Marth2,1

2Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, Glycobiology Research and Training Center, 9500 Gilman Drive-0625, University of California San Diego, La Jolla, CA 92093, USA; 3Program in Structural Biology and Biochemistry, Hospital for Sick Children, and Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada; 4Department of Biochemistry, Imperial College of Science, Technology and Medicine, London, England; 5Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA; 6Department of Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093, USA; 7Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA; 8Superfund Basic Research Center, University of California San Diego, La Jolla, CA, 92093 USA; 9Department of Paediatrics, Centre for Metabolic Disease, University of Leuven, Leuven, Belgium; 10Department of Cellular and Structural Biology, University of Colorado Health Sciences Center, Denver, CO, USA

The congenital disorders of glycosylation (CDGs) are recent additions to the repertoire of inherited human genetic diseases. Frequency of CDGs is unknown since most cases are believed to be misdiagnosed or unrecognized. With few patients identified and heterogeneity in disease signs noted, studies of animal models may provide increased understanding of pathogenic mechanisms. However, features of mammalian glycan biosynthesis and species-specific variations in glycan repertoires have cast doubt on whether animal models of human genetic defects in protein glycosylation will reproduce pathogenic events and disease signs. We have introduced a mutation into the mouse germline that recapitulates the glycan biosynthetic defect responsible for human CDG type IIa (CDG-IIa). Mice lacking the Mgat2 gene were deficient in GlcNAcT-II glycosyltransferase activity and complex N-glycans, resulting in severe gastrointestinal, hematologic, and osteogenic abnormalities. With use of a lectin-based diagnostic screen for CDG-IIa, we found that all Mgat2-null mice died in early postnatal development. However, crossing the Mgat2 mutation into a distinct genetic background resulted in a low frequency of survivors. Mice deficient in complex N-glycans exhibited most CDG-IIa disease signs; however, some signs were unique to the aged mouse or are prognostic in human CDG-IIa. Unexpectedly, analyses of N-glycan structures in Mgat2-null mice revealed a novel oligosaccharide branch on the "bisecting" N-acetylglucosamine. These genetic, biochemical, and physiologic studies indicate conserved functions for N-glycan branches produced in the Golgi apparatus among two mammalian species and suggest possible therapeutic approaches to GlcNAcT-II deficiency. Our findings indicate that human genetic disease due to aberrant protein glycosylation can be modeled in the mouse to gain insights into N-glycan-dependent physiology and the pathogenesis of CDG-IIa.

1 To whom correspondence should be addressed


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